This application is the national phase under 35 U.S.C. xc2xa7371 of PCT International Application No. PCT/JP99/05874 which has an International filing date of Oct. 25, 1999, which designated the United States of America.
The present invention relates to a method of manufacturing hard capsules based on a water-soluble cellulose derivative such as hydroxypropyl methyl cellulose (HPMC).
Hard capsules based on water-soluble cellulose derivatives such as HPMC are described in JP-A 3-279325. These hard capsules are obtained by the gelation of a water-soluble cellulose derivative such as HPMC using carrageenan as the gelling agent and using potassium ions or ammonium ions as gelling aids. The method of manufacture is comprised of preparing an aqueous capsule base solution containing the water-soluble cellulose derivative, the gelling agent and the gelling aid, dipping capsule-forming pins into the aqueous solution, then drawing the pins out of the solution and allowing the solution adhering to the outside surface of the pins to gel at room temperature so as to form a capsule film on the outside surface of the pin.
A specific method that is used involves dissolution of the gelling agent and the gelling aid in purified water at approximately 70xc2x0 C. The water-soluble cellulose derivative is dispersed in the solution, following which the dispersion is cooled to from 50 to 52xc2x0 C. The pins are dipped into the resulting solution, then drawn out to form capsules. If the temperature of the dipping solution falls outside the range of 50 to 52xc2x0 C., the jelly-like viscosity of the solution undergoes a subtle change that prevents good adherence of the solution to the capsule-forming pins during dipping and makes it difficult to obtain a uniform capsule film.
The need for strict temperature control of the jelly at such a high temperature so as to obtain uniform capsules places a large burden on equipment and other resources. It is also troublesome to maintain tight control of the operation.
The invention has been made under the above-described circumstances, and its object is to provide a method of manufacturing hard capsules which is capable of producing uniform hard capsules made of a water-soluble cellulose derivative such as HPMC without requiring strict temperature control; that is, a method which allows some play in the temperature control.
To achieve the above object, the invention provides a method of manufacturing hard capsules, characterized by comprising the steps of dispersing a water-soluble cellulose derivative in hot water and cooling the dispersion to effect dissolution of the water-soluble cellulose derivative in the water, adding and dissolving a gelling agent in the water-soluble cellulose derivative solution to give a capsule-preparing solution, dipping a capsule-forming pin into the capsule-preparing solution at a predetermined temperature, then drawing out the pin and inducing gelation of the capsule-preparing solution adhering to the pin.
In the practice of the invention, the dispersion of a water-soluble cellulose derivative such as HPMC in hot water followed by cooling effects complete dissolution of the water-soluble cellulose derivative in the water. By also subsequently dissolving a gelling agent such as carrageenan, then dipping a pin therein typically at a temperature of 35 to 50xc2x0 C. and drawing the pin out, good gelation of the capsule-preparing solution adhering to the pin is achieved.
More specifically, as discussed subsequently in Experiment, FIG. 1 is a graph of the relationship between the cooling and heating state of the HPMC solution and the solution viscosity. As shown in FIG. 1, when HPMC is dispersed in approximately 70xc2x0 C. hot water, it substantially does not dissolve in the hot water, and the resulting HPMC dispersion has a very low viscosity. However, when the HPMC dispersion is cooled, the viscosity begins rising at a temperature of about 60 to 55xc2x0 C. and reaches a maximum at a temperature of about 45 to 40xc2x0 C. (line segment A in the graph). Note that no particular pH adjustment is carried out in FIG. 1. Since it is well-known that the viscosity of HPMC and other water-soluble cellulose derivatives is affected by such factors as the pH and ionic strength, the plot in FIG. 1 serves as one model.
Prior-art methods of manufacturing HPMC hard capsules involve adding and dispersing HPMC in approximately 70xc2x0 C. water in which a gelling agent such as carrageenan and a gelling aid have already been dissolved, cooling the dispersion, dipping capsule-forming pins therein at a temperature of 52 to 50xc2x0 C. during the rise in viscosity (indicated by xe2x80x9cXxe2x80x9d in the graph), and using both the gelling effect of the gelling agent brought about by subsequent cooling and the rise in viscosity of the HPMC to produce the capsules.
As noted above, after the maximum viscosity has been reached, the HPMC solution is cooled, whereupon the viscosity decreases as indicated by B in the diagram, generally resulting in complete dissolution in water at a temperature of 30 to 40xc2x0 C. or lower. If heating is then carried out from a state where the HPMC is thoroughly dissolved in water, as shown by C in the diagram, the viscosity remains substantially unchanged up to about 45xc2x0 C. Although not shown in the diagram, the viscosity begins to rise sharply at or above about 45 to 50xc2x0 C. Carrageenan is added and dissolved at a temperature preceding the sharp rise in viscosity (e.g., at a temperature close to 40xc2x0 C. indicated by xe2x80x9cYxe2x80x9d in the diagram). In the diagram, the viscosity decreases with the addition of carrageenan. This is because the addition of a solution of carrageenan in water to the aqueous solution of HPMC dilutes the latter. When the aqueous HPMC solution containing a dissolved gelling agent is then cooled, the viscosity rises as shown by D in the diagram, with a particularly sharp rise in viscosity, namely gelation, occurring at about 35xc2x0 C.
The method of the present invention carries out capsule production by making use of, in a viscosity change pattern like that shown in FIG. 1, cooling after the solution has reached maximum viscosity and dissolution of a water-soluble cellulose derivative such as HPMC in water, subsequent addition and dissolution of a gelling agent and dipping of a capsule-forming pin at a predetermined temperature, then a rise in viscosity and gelation of the water-soluble cellulose derivative solution containing the dissolved gelling agent in a cooling or heating step.
In the inventive method, because dipping of the pin can be carried out in a temperature region where the change in viscosity of the water-soluble cellulose derivative solution (jelly) is small, even if the pin dipping temperature differs somewhat from a predetermined temperature setting, very little if any change in the jelly viscosity arises. Thus, in addition to thorough and full dissolution of the water-soluble cellulose derivative in water, a uniform capsule can be stably and reliably produced without strict temperature control of the jelly, and even with some degree of latitude in temperature control. As a result, high-quality capsules can be obtained with relatively loose control of the operation.
Furthermore, in cases where foreign matter is removed from the water-soluble cellulose derivative solution by filtration, because this can be done at a low temperature, the operation is easy to carry out. In addition, the water-soluble cellulose derivative becomes completely dissolved at a low temperature, making it possible to reliably filter off foreign matter.
Moreover, by using a method in which the water-soluble cellulose derivative is dispersed in hot water, the dispersion is cooled, and a gelling agent is subsequently added, both new and old cellulose derivative, such as HPMC that has already been formed into capsules and fresh HPMC, can be uniformly dissolved and mixed. Because the capsule film produced from this type of jelly is uniform, capsules that have already been produced can be recycled and the water-soluble cellulose derivative re-used without compromising the quality of the resulting capsules.